Since the discovery of AZT and 3TC as potent inhibitors of human immunodeficiency virus, a number of other nucleoside analogs such as FTC (emtricitabine), DAPD (andoxavir), 3TC (lamivudine or epivir), DDI (didanosine), DDC, D4T (stavudine), 2′-ara-fluoro-DDC, as well as numerous other agents have been synthesized and tested for use against HIV.
HIV is a prototype for pathogenic retroviruses, i.e., viruses that use reverse transcription to replicate. Reverse transcription mechanisms are required by those viruses having an RNA genome wherein the RNA is copied by a polymerase into DNA for subsequent replication. Certain DNA viruses use, in part, reverse transcription mechanisms to replicate such as, for example, hepatitus B virus. Reverse transcriptase is the virally-encoded polymerase used by retroviruses for this purpose.
Two nucleoside analogue reverse transcriptase (RT) inhibitors in combination with a potent protease inhibitor (e.g., nelfinavir) or a non-nucleoside RT inhibitor (e.g., sustiva) are generally recommended to achieve suppression of viral replication in current treatment protocols for HIV-1 infected individuals. Nucleoside analogue reverse transcriptase inhibitors in current use are described hereinbelow.
3′-Azido-3′-deoxythymidine (AZT, zidovudine) is administered at a dosage of 600 mg orally daily in two divided doses. The major dose-limiting toxicity of AZT is on bone marrow. Clinical trials demonstrate that therapy delays clinical evidence of disease progression in previously untreated persons with CD4+T cell counts below 500 cells/mm3. AZT is generally not used as a single agent.
Dideoxyinosine (ddI, didanosine) is administered orally as an inosine prodrug and is formulated with a buffer directed at gastric acid because of the acid lability of dideoxyadenosine. The major toxicities associated with ddI are pancreatitis and peripheral neuropathy. ddI was demonstrated to be equal or superior to AZT in antiviral and immunomodulatory effects and to provide additional clinical benefits to patients who have used AZT.
Dideoxycytosine (ddC) is a nucleoside analogue reverse transcriptase inhibitor that exhibits potent antiretroviral activity in vitro. Dose escalation of ddC is limited by peripheral neuropathy, however, and ddC is therefore used only in combination regimens or for the treatment of patients who are intolerant of, or unresponsive to, other antiretrovirals. ddC is administered at a dosage of 0.75 mg three times daily and has been used extensively in combination regimens for persons with advanced AIDS who are intolerant of other antiretroviral chemotherapeutic agents.
D4T (stavudine), a thymidine analogue, has been investigated in patients with moderate to advanced HIV-1 infection, especially those with previous AZT experience. However, peripheral neuropathy is a major side effect.
Lamivudine (3TC) is well tolerated and results in acute reductions in plasma HIV-1 RNA levels. However, a single mutation in reverse transcriptase at position 184 results in a 100-fold to 1,000-fold decrease in susceptibility to lamivudine. Any measurable degree of viral replication in the presence of the drug results in the rapid emergence of resistant mutations. Lamivudine is associated with suppression of the erythroid and myeloid elements of bone marrow. Lamivudine and AZT are being widely used as a combination with a protease inhibitor. The common resistant mutations observed after 3TC treatment are the M184V or M184I in the HIV-RT gene.
Abacavir is usually given as 600 mg, orally, daily in 2 divided doses. The drug is compromised by mutations in the reserve transcriptase (RT) gene. The efficacy of abacavir is compromised by the emergence of reverse transcriptase drug-resistant viral variants. In vitro studies have shown that the single mutations 65R, 74V, 184V, and 115F in the RT gene confer 2-3-3 fold decreases in susceptibility to abacavir. Mutants harboring 2 or 3 of these mutations exhibit approximately 10-fold resistance to the drug. In clinical studies, patients with more than 2 RT mutations showed a markedly inferior response to abacavir.
Tenofovir (lodenosine) is a fluoridated compound with similar structure and activity to ddI. Unlike ddI, stomach acids do not degrade F-ddA, so it can be administered without an antacid, thereby avoiding side effects attributable to the use of a buffer. Resistance to F-ddA is slow to emerge and the drug has shown in vitro activity against strains of HIV resistant to AZT, ddI, and ddC.
In light of rapid rates of viral replication, the highly error-prone HIV-1 reverse transcriptase, and the inability of currently available antiretroviral agents to completely inhibit HIV-1 replication, the development of resistance to antiretroviral drugs has been an inevitable consequence of drug exposure. Viral variants resistant to all antiretroviral agents in active use have been demonstrated.
The present anti-HIV protocols focus primarily on the interruption of the virus replication cycle, through the inhibition of viral enzymes involved in viral replication. Though this has resulted in some control of the virus, over one-fourth of treatment naive individuals are infected with a virus with reduced susceptibility to one or more of the currently FDA-approved drugs. Moreover, up to 3% of newly diagnosed individuals are infected with a virus that is resistant to drugs in all types of currently approved therapies.
Retroviral, especially HIV, therapy is now thought to be a life-long process. Therefore, it is crucial to develop effective treatments that can be successfully administered for long periods of time for the suppression of retroviruses, and in particular, the prevention and/or inhibition of HIV, especially those strains of HIV which have become resistant to more traditional therapies.
(−)-(1′R,4′R)-Dioxolane-thymine is a potential anti-HIV agent which has shown significant anti-HIV activity. See, C. K. Chu, et al., Tetrahedron Letters, Vol. 32, No. 31, pp. 3791-3794 (1994). This nucleoside analog has never been utilized clinically because its anti-HIV activity alone has not been considered potent enough to be a viable, clinically useful anti-HIV agent.